The Role of the Calcium-Sensing Receptor in Human Pathophysiology

The discovery of a G-protein-coupled calcium-sensing receptor (CaR) almost a decade ago has provided incontrovertible evidence of the receptor's role in the critical maintenance of systemic calcium homeostasis. Situated on the chief cells of the parathyroid glands, CaR “senses” the extracellular calcium concentration and, in turn, alters the rate of secretion of parathyroid hormone (PTH). CaR is also functionally expressed in bone, kidney, and gut-the three major organs involved in calcium homeostasis. Intracellular signal pathways to which the CaR couples include, but are not limited to, phospholipase C (PLC), Gα / Gq11, and mitogen-activated protein kinases. The receptor is widely expressed in various tissues and likely serves important cellular functions beyond the realm of maintaining systemic calcium homeostasis, i.e., cellular proliferation, differentiation, and membrane polarization etc. Functionally important mutations in the receptor have been found to cause disorders in calcium homeostasis that are due to changes in the set point for PTH secretion as well as the control of renal calcium excretion. These mutations cause hypocalcemia when the mutation activates the receptor and hypercalcemia when the mutation inactivates the receptor. Recent studies have shown the same clinical presentation caused by the presence of circulating autoantibodies to the CaR. A drug that stimulates the receptor (calcimimetic) has been effective as a medical treatment for renal secondary hyperparathyroidism.